Substituted 3-phenyl-5-alkoxy-3H- (1,3,4)-oxadiazol-2-ones, pharmaceutical composition and method for treating obesity thereof

ABSTRACT

A substituted 3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-one, compound of formula 1,  
                 
 
     wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined herein, pharmaceutical composition comprising the compound and use of the compound for inhibiting pancreatic lipase, or the prophylaxis or treatment of obesity are described.

FIELD OF THE INVENTION

[0001] The invention relates to substituted3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-ones. The invention furtherrelates to a pharmaceutical composition that comprises a substituted3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-one. The invention furtherrelates to a method for the prophylaxis or treatment of obesity, orinhibiting pancreatic lipase, PL, in a patient wherein such could beuseful comprising administering to the patient a pharmaceuticallyeffective amount of a substituted3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-one.

BACKGROUND OF THE INVENTION

[0002] Certain 5-alkoxy-1,3,4-oxadiazol-2-ones with an ortho-substitutedphenyl ring as substituent or with fused-on five- or six-membered ringshave an anthelmintic (DE-A 26 04 110) and insecticidal action (DE-A 2603 877, EP-B 0 048 040, EP-B 0 067 471).

[0003] Certain 5-phenoxy-1,3,4-oxadiazol-2-ones with anortho-substituted phenyl ring as substituent show an endoparasiticidalaction (EP-A 0 419 918).

[0004] Substituted 3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-ones with aninhibitory effect on hormone-sensitive lipase are disclosed in WO01/17981 and WO 01/66531.

SUMMARY OF THE INVENTION

[0005] The invention is directed to compounds that evidence aninhibitory effect on pancreatic lipase, PL.

[0006] A useful compound according to the invention is the substituted3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-one of formula 1,

[0007] wherein:

[0008] R¹ is

[0009] C₇-C₂₂-alkyl;

[0010] C₄-C₂₀-alkoxy-, C₆-C₁₀-aryl-, C₆-C₁₀-aryloxy- orC₄-C₁₂-alkoxy-C₂-C₄-alkoxy-substituted C₂-C₄-alkyl, wherein the aryl isa phenyl or naphthyl that is substituted one or more times by halogen,C₁-C₉-alkyl, C₁-C₈-alkyloxy, nitro or CF₃;

[0011] C₇-C₂₀-alkenyl;

[0012] 3β-cholestan-3-yl; or

[0013] phenyl that is substituted by C₆-C₁₂-alkyl or phenoxy;

[0014] and

[0015] R², R³, R⁴ and R⁵ are each, independently,

[0016] hydrogen;

[0017] halogen;

[0018] nitro;

[0019] amino;

[0020] CF₃;

[0021] OCF₃;

[0022] C₁-C₄-alkyl, C₁-C₉-alkyloxy, C₆-C₁₀-aryl-C₁-C₄-alkyloxy,C₆-C₁₀-aryloxy, C₆-C₁₀-aryl, C₁-C₄-alkylamino, di-C₁-C₄-alkyl-amino, orC₁-C₄-alkylcarbonylamino,

[0023] wherein the alkyl is optionally substituted one or more times byhalogen, hydroxy, di-C₁-C₄-alkylamino, CF₃, C₁-C₄-alkyloxy orC₁-C₄-alkyl, and the aryl is optionally substituted one or more times byhalogen, C₁-C₉-alkyl, C₁-C₈-alkyloxy or CF₃; or

[0024] C₃-C₈-cycloalkyl or C₃-C₈-cycloalkyloxy, wherein the cycloalkylis optionally substituted one or more times by halogen, CF₃,C₁-C₄-alkyloxy, C₁-C₄-alkyl or C₆-C₁₀-aryl;

[0025] or a prodrug, solvate, pharmaceutically acceptable basic salt oracid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0026] Definition of Terms

[0027] As used above, and throughout the description of the invention,the following terms, unless otherwise indicated, shall be understood tohave the following meanings.

[0028] Halogen is fluorine, chlorine or bromine, preferably fluorine orchlorine.

[0029] Alkyl, alkenyl and alkoxy as used herein may be branched orunbranched.

[0030] Patient includes both human and other mammals.

[0031] Pharmaceutically effective amount means an amount of the compoundaccording to the invention effective in producing the desiredtherapeutic effect.

[0032] Particular or Preferred Embodiments

[0033] A particular embodiment for R¹ as aryl is wherein the aryl isoptionally substituted by halogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, nitro orCF₃.

[0034] A particular embodiment for R², R³, R⁴ or R⁵ that encompassesaryl or alkyl is wherein the aryl and alkyl are optionally substitutedone, two or three times by halogen, CF₃, C₁-C₄-alkyloxy or C₁-C₄-alkyl.

[0035] A particular embodiment for R², R³, R⁴ or R⁵ that encompassescycloalkyl is wherein the cycloalkyl is optionally substituted one, twoor three times by halogen, CF₃, C₁-C₄-alkyloxy or C₁-C₄-alkyl.

[0036] A preferred compound according to the invention is a compound offormula 1 wherein: R¹ is C₇-C₂₂-alkyl, C₇-C₂₀-alkenyl, 3β-cholestan-3-ylor phenyl that is substituted by C₆-C₁₂-alkyl or phenoxy.

[0037] A further preferred compound according to the invention is acompound of formula 1 wherein: R² is hydrogen, halogen, C₁-C₄-alkyl, orC₁-C₉-alkyloxy.

[0038] A further preferred compound according to the invention is acompound of formula 1 wherein: R³ is hydrogen, C₁-C₄-alkyl, OCF₃, orC₆-C₁₀-aryl-C₁-C₄-alkyloxy, wherein the aryl is optionally substitutedby halogen.

[0039] A further preferred compound according to the invention is acompound of formula 1 wherein: R⁴ is hydrogen, OCF₃ or chlorophenoxy.

[0040] A further preferred compound according to the invention is acompound of formula 1 wherein: R⁵ is hydrogen.

[0041] A particularly preferred compound according to the invention is acompound of formula 1 wherein R¹ is C₈-C₁₆-alkyl.

[0042] A very particularly preferred compound according to the inventionis a compound of formula 1 wherein:

[0043] R¹ is C₈-C₁₆-alkyl;

[0044] R² is hydrogen;

[0045] R³ is hydrogen or OCF₃;

[0046] R⁴ is hydrogen, OCF₃ or 4-chlorophenoxy; and

[0047] R⁵ is hydrogen.

[0048] Very particularly preferred species according to the invention isthat of formula 1, which is:

[0049]5-Dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one;

[0050]5-Hexadecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one;

[0051]5-Octyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one;

[0052]5-Hexadecyloxy-3-(3-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one;

[0053]5-Hexadecyloxy-3-(4-(4-chlorophenoxy)-phenyl)-3H-(1,3,4)-oxadiazol-2-one;

[0054] 5-Octyloxy-3-phenyl-3H-(1,3,4)-oxadiazol-2-one; or

[0055]5-Tetradecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one.

[0056] The invention also encompasses all combinations of particular andpreferred aspects of the invention noted herein.

[0057] It will be apparent to those skilled in the art that certaincompounds of formula 1 can exhibit isomerism, for example geometricalisomerism, e.g., E or Z isomerism, and optical isomerism, e.g., R or Sconfigurations. Geometrical isomers include the cis and trans forms ofcompounds of the invention having alkenyl moieties. Individualgeometrical isomers and stereoisomers, including enantiomers anddiastereoisomers, within formula 1, and their mixtures, are within thescope of the invention.

[0058] Pharmaceutically acceptable salts are particularly suitable formedical applications because of their greater solubility in watercompared with the initial compounds on which they are based. These saltsmust have a pharmaceutically acceptable anion or cation. Suitablepharmaceutically acceptable acid addition salts of the compounds of theformula I are salts of inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric, metaphosphoric, nitric, sulfonic andsulfuric acids, and of organic acids such as, for example, acetic acid,benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic,glycolic, isethionic, lactic, lactobionic, maleic, malic,methanesulfonic, succinic, p-toluenesulfonic, tartaric andtrifluoroacetic acids. It is particularly preferred to use the chloridesalt and the tartaric acid salt for medical purposes. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali metalsalts (such as sodium and potassium salts) and alkaline earth metalsalts (such as magnesium and calcium salts). Salts with other anionssuch as perchlorate, hypochorite, tetrafluoroborate,hexachloroantimonate, picrate and azide, likewise fall within the scopeof the invention as useful intermediates for preparing or purifyingpharmaceutically acceptable salts and/or for use in non-therapeutic, forexample in vitro, applications.

[0059] The term “physiologically functional derivative (prodrug)” usedherein refers to any physiologically tolerated derivative of a compoundaccording to the invention, for example an ester that is able onadministration to a mammal, such as, for example, to humans, to form(directly or indirectly) such a compound or an active metabolitethereof. Such prodrugs can be metabolized in vivo to a compound of theformula 1. These prodrugs may themselves be active or not.

[0060] The compound of formula 1 may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compound of formula 1 fall within the scope ofthe invention and are a further aspect of the invention.

[0061] “Solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolable solvates. Representativesolvates include ethanolates, methanolates, and the like.

[0062] The amount of a compound of formula 1 necessary to effect themethod according to the invention, i.e., to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) perday and per kilogram of body weight, for example 3-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.3 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Infusion solutions suitable for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampoules forinjections may contain, for example, from 1 mg to 100 mg, and singledose formulations that can be administered orally, such as, for example,tablets or capsules, may contain, for example, from 1.0 to 1000 mg,typically from 10 to 600 mg. In the case of pharmaceutically acceptablesalts, the above weight data are based on the weight of the salt of thecompound of formula 1. The compound of formula 1 can be used as notedherein by itself, but it is preferably in the form of a pharmaceuticalcomposition with a compatible carrier. The carrier must, of course, becompatible in the sense of compatibility with other ingredients of thecomposition and not be harmful to the patient's health. The carrier maybe a solid or a liquid or both and is preferably formulated with thecompound as single dose, for example as tablet, which may contain from0.05% to 95% by weight of the active ingredient. Further an additionalpharmaceutically active substance may likewise be present with thecompound of formula 1. The pharmaceutical composition according to theinvention is produced by one of the known pharmaceutical methods thatessentially consist of mixing the ingredients with pharmacologicallyacceptable carriers and/or excipients.

[0063] Pharmaceutical compositions according to the invention are thosesuitable for oral, rectal, topical, peroral (for example sublingual) andparenteral (for example subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the nature of thecompound of the formula 1 used in each case. Coated formulations andcoated slow-release formulations also fall within the scope of theinvention. Acid- and gastric fluid-resistant formulations are preferred.Suitable gastric fluid-resistant coatings comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethyl-cellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

[0064] Suitable pharmaceutical compounds for oral administration may bein the form of separate units such as, for example, capsules, cachets,pastilles or tablets, each of which contains a defined amount of thecompound of the formula 1; as powder or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method that includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. In general,-thecompositions are produced by uniform and homogeneous mixing of theactive ingredient with a liquid and/or finely dispersed solid carrier,after which the product is shaped if necessary. Thus, for example, atablet can be produced by compressing or shaping a powder or granules ofthe compound, where appropriate with one or more additional ingredients.Compressed tablets may be produced by tabletting the compound infree-flowing form, such as, for example, a powder or granules, whereappropriate mixed with a binder, lubricant, inert diluent and/or one (ormore) surface-active/dispersing agents in a suitable machine. Shapedtablets can be produced by shaping, in a suitable machine, the compoundthat is in powder form and has been moistened with an inert liquiddiluent.

[0065] Pharmaceutical compositions suitable for peroral (sublingual)administration comprise suckable tablets that contain a compound offormula 1 with a flavoring, normally sucrose, and gum arabic ortragacanth, and pastilles that contain the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

[0066] Suitable pharmaceutical compositions for parenteraladministration comprise preferably sterile aqueous preparations of acompound of formula 1, which are preferably isotonic with the blood ofthe intended recipient. These preparations are preferably administeredintravenously, although administration can also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions according to the invention generally contain from 0.1 to 5%by weight of the active compound.

[0067] Suitable pharmaceutical compositions for rectal administrationare preferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula 1 with one or more conventionalsolid carriers, for example cocoa butter, and shaping the resultingmixture.

[0068] Suitable pharmaceutical compositions for topical use on the skinare preferably in the form of an ointment, cream, lotion, paste, spray,aerosol or oil. Carriers that can be used are petrolatum, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition, forexample from 0.5 to 2%.

[0069] Transdermal administration is also possible. Suitablepharmaceutical compositions for transdermal applications may be in theform of single plasters that are suitable for long-term close contactwith the patient's epidermis. Plasters of this type suitably contain theactive ingredient in an aqueous solution that is buffered whereappropriate, dissolved and/or dispersed in an adhesive or dispersed in apolymer. A suitable active ingredient concentration is about 1% to 35%,preferably about 3% to 15%. As a particular option, the activeingredient can be released by electrotransport or iontophoresis asdescribed, for example, in Pharmaceutical Research, 2 (6): 318 (1986).

[0070] The compounds according to the invention of formula 1 can beprepared in various ways by methods known per se.

[0071] For example, substituted3-phenyl-5-alkoxy-3H-(1,3,4)-oxadiazol-2-ones of formula 1 can beprepared by reacting a hydrazine of formula 2 with a chloroformic esterof formula 3 or other reactive carbonic ester derivative, wherein R¹,R², R³, R⁴ and R⁵ are as defined above, to give a compound of formula 4,which is acylated with phosgene (for example, to give a compound offormula 5), carbonyldiimidazole, diphosgene or triphosgene, cyclized andconverted where appropriate by further chemical modification of theradicals R²-R⁵, such as, for example, by reduction of nitro to aminoradicals by known processes, and subsequent acylation or alkylation,into compounds of the formula 1. Since acids are usually liberated inthese reactions, promotion is advisable by adding bases such aspyridine, triethylamine, sodium hydroxide solution or alkali metalcarbonates. The reactions can be carried out in wide temperature ranges.It has proved advantageous as a rule to operate at 0° C. to the boilingpoint of the solvent used. Examples of solvents employed are methylenechloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethylether.

[0072] The hydrazines of formula 2 can be prepared by known methods, forexample by diazotization of the corresponding anilines and

[0073] subsequent reduction by known methods or by nucleophilicsubstitution of suitably substituted phenyl derivatives 6 (X=F, Cl, Br,I, OSO₂CF₃) with hydrazine hydrate. Such suitable phenyl derivatives maybe nitro-substituted halobenzenes, preferably fluoro- andchloronitrobenzenes, from which the compounds according to the inventioncan be prepared by known methods at a suitable point in the syntheticroute by reduction and reaction with acylating or alkylating agents suchas, for example, acid chlorides, anhydrides, isocyanates, chloroformicesters, sulfonyl chlorides or alkyl and arylalkyl halides, or byreductive alkylation with aldehydes.

[0074] The effect of the compounds according to the invention of formula1 was tested using the following enzyme assay system: [lacuna]

[0075] The compounds of formula 1 show an inhibitory effect onpancreatic lipase (PL). As PL inhibitors, they are able to preventabsorption of fat consumed with the diet and thus lead to a reduction inthe fat uptake and the body weight or prevent an increase in bodyweight. The compounds of formula 1 are particularly suitable fortreating obesity but may also have a very beneficial effect in variousmetabolic derangements such as, for example, diabetes, andcardiovascular disorders such as, for example, hypertension andmyocardial infarction.

[0076] The invention further relates to a method for the prophylaxis ortreatment of obesity, in a patient in need thereof, comprisingadministering to the patient a pharmaceutically effective amount atleast one compound of formula 1.

[0077] The activity of the compounds was assayed as follows:

[0078] 1. Preparation of the Substrate:

[0079] 80 μL of tripalmitin (85 mM in chloroform) are mixed with 5 μL ofglycerol tri[9,10(n)-³H]oleate (5 mCi/mL in toluene) in a 12 mLpolypropylene vessel. Evaporation in a rotary evaporator (50° C.) andaddition of 4 mL of 200 mM Tris/HCl (pH 7.6), 0.8% TX-100 are followedby ultrasound treatment of the mixture (Branson B-12 sonifier, outputlevel 4, 3×2 min with 1 min intervals on ice) until a homogeneous milkysuspension is produced.

[0080] 2. Assay:

[0081] Lipase buffer: 80 mM Tris/HCl (pH 7.6), 600 mM NaCl, 8 mM CaCl₂,8 mM benzamidine, 2 mM Pefabloc (Roche Biochemicals) (add the inhibitorsonly on the day of the assay)

[0082] Pancreatic lipase: Enriched preparation from porcine pancreas(Sigma order No. L-0382) dissolved in lipase buffer (100 000 units/500μL)

[0083] Procedure:

[0084] 5 μL of test substance (in 100% DMSO) or DMSO (control) are mixedwith 10 μL of substrate and 5 μL of lipase (in this sequence) andincubated at 30° C. (Eppendorf Thermomixer, 350 min⁻¹) for 30 min. Afteraddition of 325 μL of methanol/chloroform/n-heptane (10/9/7) and 105 μlof 0.1 M K₂CO₃, 0.1 M H₃BO3 (pH 10.5 adjusted with 1 M KOH) and vigorousmixing, the phases are separated by centrifugation (8000 rpm, Eppendorfcentrifuge, 4° C.). 140 μL portions of the aqueous supernatant (containsthe liberated radiolabeled oleate; 70% recovery) are transferred into 20mL scintillation vials and mixed with 6 mL of scintillation cocktail(Beckman ReadySafe). After vigorously mixing and incubating at roomtemperature for 2 h, the radioactivity is measured in a liquidscintillation counter (Beckman, L8008, tritium channel with quenchcurve, measurement time 20 min).

[0085] Evaluation:

[0086] Substances are routinely tested in each concentration in threeindependent incubation mixtures each with duplicate determination afterphase separation (SD<0.02). Background values (reaction under the sameconditions but without lipase) are subtracted from all values(corresponds predominantly to the content of glycerol trioleate or freeoleate in the substrate preparation in the aqueous phase, <5% of theradioactivity employed). The inhibition of the pancreatic lipaseenzymatic activity by a test substance is determined by comparison withan uninhibited control reaction (presence of lipase=0% inhibition;absence of lipase 100% inhibition in each case after backgroundcorrection). The IC₅₀ is calculated from an inhibition plot with up to 8concentrations of the test substance. The software package GRAPHIT(Elsevier-BIOSOFT) is used for curve fitting and IC₅₀ determination.

[0087] The compounds showed the following effect in this assay: CompoundExample No.: IC₅₀ (μM) 1 0.03 2 0.25 3 0.35 4 2.5 5 2.0 6 0.9 15 0.6

[0088] The following examples illustrate the preparation methods ingreater detail without restricting them.

EXAMPLES Example 1

[0089]5-Dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0090] 0.43 mL of dodecyl chloroformate was cautiously added dropwise toa mixture consisting of 0.84 g of 4-trifluoromethoxyphenylhydrazine, 15mL of NMP and 2 mL of pyridine while cooling in ice, and the mixture wasthen stirred for 2 hours while slowly warming to room temperature. Afterdilution with 50 mL of water, extraction by shaking was carried out with30 mL of methylene chloride, the organic phase was dried with sodiumsulfate and, while stirring and cooling in ice, 5 mL of pyridine and 3mL of a 20% strength solution of phosgene in toluene were addeddropwise. This mixture was allowed to stand overnight at roomtemperature and was diluted with a further 10 mL of methylene chlorideand then washed 3 times with water. After drying over sodium sulfate,the mixture was concentrated in vacuo and the product was purified bycolumn chromatography (silica gel, solvents:methanol:methylenechloride=2:98).

[0091] Yield: 0.85 g, M.p.: 41° C.

[0092] The compounds of the following examples were preparedanalogously:

Example 2

[0093]5-Hexadecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0094] M.p.: 56° C.

Example 3

[0095]5-Octyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0096] M.p.: oil

Example 4

[0097]5-Hexadecyloxy-3-(3-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0098] M.p.: 53° C.

Example 5

[0099]5-Hexadecyloxy-3-(4-(4-chlorophenoxy)-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0100] M.p.: 52° C.

Example 6

[0101] 5-Octyloxy-3-phenyl-3H-(1,3,4)-oxadiazol-2-one

[0102] M.p.: 38° C.

Example 7

[0103] 5-Octyloxy-3-(3-fluoro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0104] M.p.: oil

Example 8

[0105] 5-Hexadecyloxy-3-(3-fluoro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0106] M.p.: 58° C.

Example 9

[0107] 5-Hexadecyloxy-3-(3-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0108] M.p.: 65° C.

Example 10

[0109] 5-Hexadecyloxy-3-phenyl-3H-(1,3,4)-oxadiazol-2-one

[0110] M.p.: 63° C.

Example 11

[0111] 5-Hexadecyloxy-3-(4-nitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0112] M.p.: 72° C.

Example 12

[0113] 5-Hexadecyloxy-3-(4-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0114] M.p.: 66° C.

Example 13

[0115] 5-Hexadecyloxy-3-(4-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0116] M.p.: 73° C.

Example 14

[0117]5-Decyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0118] M.p.: oil

Example 15

[0119]5-Undecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0120] M.p.: 38° C.

Example 16

[0121]5-Tetradecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0122] M.p.: 46° C.

Example 17

[0123]5-Tridecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0124] M.p.: 50° C.

Example 18

[0125]5-(2-(2-Hexyloxy-ethoxy)-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0126] M.p.: oil

Example 19

[0127]5-((Z)-Octadec-9-enyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0128] M.p.: oil

Example 20

[0129]5-(Dodecyloxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0130] M.p.: oil

Example 21

[0131]5-(2-(4-Fluorophenyl)-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0132] M.p.: 60° C.

Example 22

[0133]5-((3β-Cholestan-3-yl)-oxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0134] M.p.: 127° C.

Example 23

[0135]5-(2-Butoxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0136] M.p.: resin

Example 24

[0137]5-(7-Phenyl-heptyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0138] M.p.: resin

Example 25

[0139]5-(Docosyloxy-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0140] M.p.: 71° C.

Example 26

[0141]5-(2-(1-Naphthyloxy)-ethoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0142] M.p.: resin

Example 27

[0143]5-(4-Octylphenoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0144] M.p.: resin

Example 28

[0145]5-(3-Phenoxy-phenoxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0146] M.p.: resin

Example 29

[0147]5-(Dodecyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0148] M.p.: 41° C.

Example 30

[0149] 5-(Dodecyloxy)-3-(3,4-dichloro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0150] M.p.: 74° C.

[0151] Example 31

[0152] 5-(Dodecyloxy)-3-(3,5-dichloro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0153] M.p.: 48° C.

Example 32

[0154] 5-(Dodecyloxy)-3-(3-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0155] M.p.: 51° C.

Example 33

[0156] 5-(Dodecyloxy)-3-(4-methoxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0157] M.p.: 57° C.

Example 34

[0158] 5-(Dodecyloxy)-3-(3-nitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0159] M.p.: 64° C.

Example 35

[0160]5-(Dodecyloxy)-3-(3-trifluoromethyl-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0161] M.p.: 43° C.

Example 36

[0162]5-(Dodecyloxy)-3-(3,5-bis-trifluoromethyl-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0163] M.p.: oil

Example 37

[0164] 5-(Dodecyloxy)-3-(4-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0165] M.p.: 65° C.

Example 38

[0166] 5-(Dodecyloxy)-3-(3-fluoro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0167] M.p.: 44° C.

Example 39

[0168]5-(Dodecyloxy)-3-(3-(4-fluorobenzyloxy)-4-nitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0169] M.p.: 71° C.

Example 40

[0170]5-(Dodecyloxy)-3-(2-methyl-4-nitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0171] M.p.: 63° C.

Example 41

[0172]5-(Dodecyloxy)-3-(3-methyl-4-nitro-phenyl)-3H-(1,3,4)-oxadiazol-2-one

[0173] M.p.: 62° C.

We claim:
 1. A compound of formula 1

wherein: R¹ is C₇-C₂₂-alkyl; C₄-C₂₀-alkoxy-, C₆-C₁₀-aryl-, C₆-C₁₀-aryloxy- or C₄-C₁₂-alkoxy-C₂-C₄-alkoxy-substituted C₂-C₄-alkyl, wherein the aryl is a phenyl or naphthyl that is substitued one or more times by halogen, C₁-C₉-alkyl, C₁-C₈-alkyloxy, nitro or CF₃; C₇-C₂₀-alkenyl; 3β-cholestan-3-yl; or phenyl that is substituted by C₆-C₁₂-alkyl or phenoxy; and R², R³, R⁴ and R⁵ are each, independently, hydrogen; halogen; nitro; amino; CF₃; OCF₃; C₁-C₄-alkyl, C₁-C₉-alkyloxy, C₆-C₁₀-aryl-C₁-C₄-alkyloxy, C₆-C₁₀-aryloxy, C₆-C₁₀-aryl, C₁-C₄-alkylamino, di-C₁-C₄-alkyl-amino, or C₁-C₄-alkylcarbonylamino, wherein the alkyl is optionally substituted one or more times by halogen, hydroxy, di-C₁-C₄-alkylamino, CF₃, C₁-C₄-alkyloxy or C₁-C₄-alkyl, and the aryl is optionally substituted one or more times by halogen, C₁-C₉-alkyl, C₁-C₈-alkyloxy or CF₃; or C₃-C₈-cycloalkyl or C₃-C₈-cycloalkyloxy, wherein the cycloalkyl is optionally substituted one or more times by halogen, CF₃, C₁-C₄-alkyloxy, C₁-C₄-alkyl or C₆-C₁₀-aryl; or a prodrug, solvate, pharmaceutically acceptable basic salt or acid addition salt thereof.
 2. A compound according to claim 1, wherein R¹ is C₇-C₂₂-alkyl, C₇-C₂₀-alkenyl, 3β-cholestan-3-yl, or phenyl that is substituted by C₆-C₁₂-alkyl or by phenoxy.
 3. A compound according to claim 1, wherein R² is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₉-alkyloxy.
 4. A compound according to claim 1, wherein R³ is hydrogen, C₁-C₄-alkyl, OCF₃, or C₆-C₁₀-aryl-C₁-C₄-alkyloxy, wherein the aryl is optionally substituted by halogen.
 5. A compound according to claim 1, wherein R⁴ is hydrogen, OCF₃ or chlorophenoxy.
 6. A compound according to claim 1, wherein R⁵ is hydrogen.
 7. A compound according to claim 1, wherein: R¹ is C₇-C₂₂-alkyl, C₇-C₂₀-alkenyl, 3β-cholestan-3-yl, or phenyl that is substituted by C₆-C₁₂-alkyl or by phenoxy; R² is hydrogen, halogen, C₁-C₄-alkyl or C₁-C₉-alkyloxy; R³ is hydrogen, C₁-C₄-alkyl, OCF₃, or C₆-C₁₀-aryl-C₁-C₄-alkyloxy, wherein the aryl is optionally substituted by halogen; R⁴ is hydrogen, OCF₃ or chlorophenoxy; and R⁵ is hydrogen.
 8. A compound according to claim 1, wherein R¹ is C₈-C₁₆-alkyl.
 9. A compound according to claim 1, wherein R¹ is C₈-C₁₆-alkyl; R² is hydrogen; R³ is hydrogen or OCF₃; R⁴ is hydrogen, OCF₃ or 4-chlorophenoxy; and R⁵ is hydrogen.
 10. A pharmaceutical composition comprising at least one compound of formula 1 as claimed in claim 1 and a pharmaceutically acceptable carrier or excipient.
 11. A method for the prophylaxis or treatment of obesity, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of formula 1 as claimed in claim
 1. 12. A method for inhibiting pancreatic lipase, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of a compound of formula 1 as claimed in claim
 1. 